138 Tetanus

Tetanus is an acute disease caused by the production of a neurotoxin, tetanospasmin, by a bacterium, Clostridium tetani, when the spores of the organism enter a wound, and develop into the toxin-producing vegetative form.

Etiology and Epidemiology

C. tetani is an obligate anerobe, a spore-forming, gram-positive motile rod. The terminal spore caused the organism to be called the “drumstick” rod. The protein toxin, tetanospasmin, blocks acetylcholine release at the motor end-plates. The toxin travels up the nerve trunks, as well as fixing directly on nerve cells. The spinal cord is the primary target organ, with chromatolysis of the motor neurons and inhibi­tion of antagonists accounting for the spasm and rigidity that characterize the disease. Toxin fixation to central nervous system neurons may lead to sei­zures; involvement of the sympathetic nervous sys­tem may evoke vascular irregularities.

Humans may be considered accidental interven­ers in the life cycle of the organism, which is a soil saprophyte and a harmless inhabitant of the intes­tines of many herbivores. The organism requires a wound to invade mammals. Traumatic, surgical, dental, umbilical, burn, and cosmetic wounds are the most common causes of infection in humans. “Skin popping” of addictive drugs, insect bites, and nonmedical abortions are less common causes of infection. As an obligate anaerobe, the organism can reproduce and produce toxin only when local oxidation-reduction processes reduce tissue oxygen to near zero; deep, infected wounds are thus ideal culture media.

There may be 300,000 to 500,000 cases of tetanus a year worldwide, with perhaps 120,000 of those being neonates whose umbilical wounds become in­fected.

Clinical Manifestations, Diagnosis, and Pathology

There is no special characteristic or diagnostic pa­thology. Lysis of myofibrils and muscle bleeding are secondary to the muscle spasm. The usual incuba­tion period ranges from 2 to 14 days after wounding. Cases of “dormant” tetanus have been reported after several months, probably because spores have re­mained in a closed wound as a silent abscess. The diagnosis is based entirely on the history and the clinical findings; there are no specific laboratory findings. The differential diagnosis includes strych­nine poisoning and dystonic reactions to phenothia­zines and metoclopramide.

The clinical manifestations are usually classified into three forms: _

1. Localized tetanus presents with spasm near the site of the injury, usually in an extremity. The fatality rate is 1 percent or less.

2. Generalized tetanus, the more common form, is marked by the classic trismus (lockjaw), fixed grin (risus sardonicus), and backward arching of the trunk (opisthotonos). Tonic seizures of the muscle groups occur in spasms, lead to rigidity, and are very painful. They may be precipitated by any stimulus. Pneumonia may follow respiratory mus­cle involvement or laryngeal spasm with as­piration. Cardiovascular disturbances are com­mon, especially vasoconstriction and a labile blood pressure. Severe spasms may cause vertebral frac­tures. The course of this form, in survivors, is from 1 to 2 weeks.

3. Cephalic tetanus, an uncommon form of the dis­ease, follows facial wounds, involves the facial nerves, and may be followed by generalized tetanus.

4. Neonatal tetanus following infection of the umbili­cal cord (discussed in the next chapter) usually begins by the third to tenth day after birth, and then progresses to generalized tetanus.

Death from tetanus is usually due to respiratory failure with hypoxia or pneumonia, and occasionally to circulatory collapse, especially in patients over 60 years old.

Treatment

Treatment may be summarized as measures to de­crease the presence of the organism: debridement of the wound and antibiotics; neutralization of the toxin by antitoxin; and control of the effects of the toxin by drugs with specific neuropharmacological effects. Curarization and artificial respiration for 2 weeks have been used in severe cases. Careful con­tinuous nursing care is essential.

History

A man who was struck from behind by a sharp dart a little below the neck had a wound which did not look serious because it did not go deep. But sometime later when the point had been extracted the patient was seized with backward-bending convulsions like those of opisthotonus. His jaws were locked, and any liquid that he attempted to swallow was returned through his nostrils. He died on the second day.

So Hippocrates recorded an obvious case of tetanus. At least one other case is recorded in the same vol­ume. In Diseases III, the general case is given: ^,*[W]hen tetanus occurs, the jaws become as hard as wood, patients cannot open their mouths... their backs become rigid...he suffers great pain...gener­ally dies on the third, fifth, seventh or fourteenth day — if he survives that many, he recovers.” Further it is noted that “the patient is drawn backwards... his pains are violent... his elbows become flexed... he holds his fingers in a fist... vomits through his nostrils. If one survives for fourteen days, he recov­ers.” The treatment regimens varied: “pepper, black, hellbore, fat bird soup, vapour baths, cold water baths,” and “phlobotomy relieves Imnbar tetanus.”

But the terseness of the aphorism “A convulsion supervening upon a wound is deadly” may mark the more general outcome of a case of generalized teta­nus. Certainly Aretaeus (Adams 1956), writing some 700 years later, found tetanus to be “An inhu­man calamity! An incredible sight! A spectacle pain­ful even to the beholder! An incurable malady!” He believed the prayers of spectators for the death of the patient to be useful, “being a deliverance from the pains.” He also pitied the attending physician’s in­ability to afford relief, “for if he should wish to straighten the limbs, he can only do so by cutting and breaking those of a living man.” It is a “great misfortune of the physician.” Aretaeus, after an ex­cellent clinical description of the disease, urged a wide variety of therapeutic maneuvers, including special diets, forcing liquids, a quiet house, phlebot­omy, massage with oils, fomentations, cupping, spe­cific treatment of any wound, and more.

The clinical descriptions have not been bettered. Therapy has changed, but it is possible that the number of survivors “after the fourteenth day” may not have markedly improved. William Osler (1892), in his seminal text, noted the clinical and epi­demiological data given above, cited Hippocrates, and summarized the unchanged clinical findings. He found an 80 percent rate mortality within 4 days. Therapy had improved: The nasogastric tube was in use for feeding and hydration, morphine for seda­tion, and chloroform for muscle relaxation. He em­phasized antiseptic care of the wound. It is fair to say that from Hippocrates to Osler - and to today — there have been no changes in diagnostic tech­niques, and there has been only a small reduction in mortality rates in established cases. Tetanus is a disease that must be prevented, and prevention had to begin with isolation of the organism and advances in immunology.

Isolation of the Tetanus Organism

The discovery of the tetanus organism was part of the microbiological revolution that proved the theory that a specific organism caused a specific disease. In 1884 Arthur Nicolaier produced tetanus-like symp­toms and death by injecting soil samples into ani­mals. He isolated a rod-shaped bacillus and sug­gested that it secreted a toxin resembling strychnine in its action. He did not isolate the organism in pure culture. Neither did D. Rosenbach in 1886, although he was able to produce classic tetanus in guinea pigs by injecting tissue from a fatal human case. He did describe the “drumstick” appearance and correctly deduced that these were terminal spores. It remained for Shibasaburo Kitasato to isolate the organism in pure culture, in 1889, from a fatal case of a soldier in Berlin. He described the anaerobic culture require­ments, said he had confirmed Nicholaier’s observa­tions, and also concluded that the clinical effects were due to a toxin. The study of tetanus toxin and anti­toxin followed directly and in parallel with the re­search of Emil Behring and Kitasato on diphtheria toxin, a much more important disease.

Tetanus Toxin and Antitoxin

Tetanus and diphtheria investigations provided the framework upon which Behring built his under­standing of the principles of serum therapy. In an 1892 (1892b) paper, he argued that the serum of a patient should contain material protective and cura­tive for another individual with the disease. In a series of studies, he and his co-workers proved this point in animal studies, but did not recommend se­rum use in humans until the mechanism of action was better understood. They noted that even if treat­ment of the animal began very early, at least 1,000 times as much antitoxin was needed to cure as to protect before infection, and that, as the symptoms became general, the antitoxin was useless in any amount.

The availability of horse antitoxin soon led to clini­cal trials, with widely varying results. Analysis eventually showed that antitoxin had to be given very early in the disease; that dosage - empirical at first - was critical; and that it was essentially use­less once the toxin was fixed to neurons and the patient was symptomatic. As Henry Parish (1965) and E. Haberman (1978) both suggest, better under­standing of wound care and more aseptic surgery accompanied the rising rate of successful use of anti­toxin and a decreased death rate, especially in se­lected populations like soldiers.

Given that soldiers often have fought in well- manured farmland and do not have clean skins, and that until very recently armies lived in close proxim­ity to horses used for transport and cavalry, it is not surprising that tetanus was a common problem in wounded soldiers. In 1808, for example, the rate of tetanus before immunization was 12.5 per 1,000; by contrast, the rate was only 0.04 per 1,000 in World War ∏ (Boyd 1958).

It was World War I that saw the general introduc­tion of early, near-universal use of antitoxin, accom­panied by meticulous debridement of wounds. The effect of these measures may be seen in the British army. There was an incidence of 8 per 1,000 wounded from August to October 1914.

Tetanus Toxoid

Although Arthur Silverstein (1989) credits Paul Ehr­lich with the first discussion of toxoids, the practical use of formaldehyde to produce a toxoid (a formalin- inactivated antitoxin) was introduced for tetanus by Gaston Ramon in 1927 following the preliminary work by P. Descomby in 1924. As opposed to the passive immunity conferred by antitoxin, the toxoid produced an active immunity that would protect against tetanus. Also in 1927, Ramon along with Charles Zoeller tested the immunogenicity of the toxoid in humans, and later worked out the duration of immunity and the timing and effect of booster doses.

A fluid toxoid was in use because of its harmless­ness and its efficacy (although it caused more local reactions than does the modern aluminum phos­phate absorbed vaccine). This toxoid, a combined diphtheria-tetanus toxoids vaccine, was given to in­fants in parts of France in the late 1920s and, by regulation, to French soldiers in 1931.

Immunization with the much more epidemiologi- cally important diphtheria toxoid began in the 1920s in parts of the United States and just before World War II in Britain. The absorbed tetanus toxoid was used by the armies of Britain, France, and Canada by 1939; the United States began its use in 1941. During World War II, the American army had 5 fatal tetanus cases (2 in nonimmunized patients) and 7 nonfatal cases (all in immunized patients) in over 500,000 wounded soldiers. The reaction rate to the immunization series of three doses was 21 per 100,000, none fatal.

After World War II, the routine use of a combined vaccine of diphtheria and tetanus toxoids (DT) was urged for childhood immunization. Soon the triple vaccine, with pertussis added (DPT), became legally required for school admission in the United States. Childhood immunization programs in Europe vary, but tend to be on similar schedules and under simi­lar laws. Nonfatal anaphylactic reactions occur at a rate of 1 per 1.5 to 2 million doses. The benefit/risk ratio for tetanus immunization is thus extraordi­narily good. A worldwide infant and child immuniza­tion campaign, coupled with a booster upon injury, would essentially eliminate the disease as a clinical entity.

Robert J. T. Joy

Bibliography ^r

Adams, Francis. 1956. The extant works of Aretaeus, the Cappadocian. London.

Beaty, Harry N. 1987. Tetanus. In Harrison’s principles of internal medicine, ed. Eugene Braunwald et al., 558­61. New York.

Behring, Emil. 1892a. Das Tetanusheilserum und seine Anwendung auf tetanuskranke Menschen. Leipzig.

1892b. Die Blutserumtherapie bei Diphtherie und Teta­nus. Zeitschrift filr Hygiene und Infektionskrankhei- ten 12: 1—9.

Behring, Emil, and Shibasaburo Kitasato. 1890. Ueber das Zustandekommen der Diphtherie-Immunitat und der Tetanus-Immunitat bei Thiereu. Deutsche Medi- zinische Wochenschrift 16: 1113—45.

Behrman, Richard E., and Victor C. Vaughn, III. 1983. Nelson textbook of pediatrics. 686—9. Philadelphia.

Boyd, John. 1958. Tetanus in two world wars. Proceedings of the Royal Society of Medicine 52:109—110.

Chamberlain, Weston P., and Frank W. Weed. 1926. Medi­cal department of the United States Army in the World War, Vol. VI: Sanitation. Washington, D.C.

Courtois-Suffit, M., and R. Giroux. 1918. The abnormal forms of tetanus. London.

Davis, Bernard D., et al., eds. 1990. Microbiology. Philadelphia.

Dowling, Harry P. 1977. Fighting infection. Cambridge, Mass.

Haberman, E. 1978. Tetanus. In Handbook Ofclinical neu­rology, Vol. 33, Part 1, ed. P. J. Ninken and G. W. Bruyn, 491—547. New York.

Hill, Gale B., Suydam Osterhaut, and Hilda P. Willet. 1988. Clostridium. In Zinsser microbiology, ed. Wolf­gang K. Jolik et al., 545-48. Norwalk, Conn.

Hippocrates. 1931. Aphorisms V, trans, and ed. W. H. S. Jones. Cambridge.

1973. Epidemics V. In Greek medicine, trans. E. D. Phil­lips, 70-1. London.

Kitasato, Shibasaboro. 1889. Ueber den tetanus bacillus. Zeitschrift filr Hygiene und Infektionskrankheiten 7: 225-34.

Long, Arthur P. 1955. The Army immunization program. InPersonal health measures and immunization: Medi­cal department of the U.S. Army in World War II, ed. Ebbe C. Hoff, 271-341. Washington, D.C.

National Institute of Medicine. 1985. Vaccine supply and innovation, ed. Jay P. Sanford. Washington, D.C.

Nicolaier, Arthur. 1884. Ueber infectiδsen Tetanus. Deutsche Medizinische Wochenschrift 10:842—44.

Osler, Sir William. 1892. The principles and practice of medicine. New York.

Parish, Henry J. 1965. A history Ofimmunization. London. Ramon, Gaston, and P. Descomby. 1927. L¹Anatoxine te­tanique et la prophylaxe du tetanos chez Ie cheval et les animaux domestiques. Annales de ITnstitut Pas­teur 41: 835-47.

Ramon, Gaston, and Charles Zoeller. 1927. L’Anatoxine tstiffening of the jaw, resembling a smile. The mouth will not open fully, resulting in a condition that has become known as risus sardonicus. Patients often have their legs and arms partially flexed, arms crossed over their abdomen, hands clenched, excessive flexion of the toes, stifled cry, and wrinkled face. Their body temperatures can reach 100^o or higher. Sucking is impaired, thus making regular nursing impossible. That and general fussi­ness are the first symptoms most mothers notice. Respiratory complications commonly arise. Infants who die within 48 hours generally succumb to uncon­trolled spasms or intense congestion of the liver, lungs, or brain. Newborns who die from the disease after 2 days generally die from bronchopneumonia. Other complications include aspiration pneumonia, acute gastroenteritis, and umbilical hernia.

Treatment

The best means of controlling the disease are those that prevent the organism from entering - namely ensuring sterile conditions for the birth. The umbili­cus should be treated conservatively and cleaned with hydrogen peroxide; foreign objects should be removed, and thimerosal (Merthiolate) applied.

Most medical observers conclude that in order to lessen the incidence of neonatal tetanus in Third World nations, obstetrical procedures must be im­proved by teaching traditional birth attendants about sepsis. The transfer of maternal tetanus anti­bodies across the placenta has been found to be effective in conferring passive immunity to the neo­nate for several months, though it is better if the mother is immunized before, rather than during, pregnancy. Nevertheless, researchers have recently discovered that injections of absorbed tetanus tox­oid given to pregnant women who have not been inoculated previously for tetanus (at least 2 injec­tions spaced about 6 weeks apart) can successfully prevent infant infection.

Babies who do develop neonatal tetanus are often sedated with phenobarbital and chlorpromazine given intramuscularly, although diazepam is fre­quently used now because it works quickly. Antibiot­ics are also administered. The infant should be kept quiet, fed through a tube, and, if having difficulty breathing, given mouth-to-mouth resuscitation. The aim is first to control muscle spasms with sedatives and then to keep the baby breathing with a tracheot­omy and a respirator if available. Medical atten­dants in hospitals or clinics commonly place the in­fant in intensive care, give an antitoxin, apply antibacterial therapy, and ensure airway clearance.

History and Geography

The term tetanus is from the Greek verb tano, mean­ing “to stretch.” Hippocrates described three vari­eties of the infant disease. Aristotle noted infant con­vulsions that occurred before the seventh day. Galen first named the disease trismus. Moschion (Muscio), writing about three centuries later, claimed that it was caused by stagnant blood in the umbilical cord, as did Andre Levret and others some 1,500 years after Galen. Indeed, by the early nineteenth century, doc­tors were still attributing neonatal tetanus to this cause as well as a variety of others, including irrita­tion within the intestinal canal, poverty, filth, poor diet, falls, impure atmosphere, rough handling, a vaginal disease, cold or sea air, costiveness, smoke from chimneys, and mismanagement by female mid­wives. In 1793 M. Bartram of South Carolina as­cribed the disease to the umbilicus, and his theory generated much debate. Some physicians urged cleanliness and washing the umbilicus with a weak solution of silver nitrate and dressing the area with an ointment formed of lard and lead acetate.

But attention strayed again from the umbilicus. A study at the Dublin Lying-In Hospital in 1782 noted that of 17,650 infants bom, 2,944 died within a fort­night from neonatal tetanus. The institution’s im­pure atmosphere and poorly ventilated chambers were blamed for the high rate. In 1846 J. Marion Sims concluded that a depression of the occipital bone during birth caused the disease, and he urged his colleagues to observe bone formation closely in newborns.

In 1818 Abraham Colles, however, first noted the similarity between neonatal tetanus and tetanus and attributed its incidence to inflammation and ulceration of the umbilicus. He suggested that air be purified, that the umbilicus be dressed with spirits of turpentine, and that the baby be plunged into cold water. Efforts were made to bleed patients to remove the noxious influences and produce relaxation. Dur­ing the nineteenth century, accounts demonstrate a 99 percent fatality for those who were affected. No disease of infancy was more fatal, and few parents saw any reason to call a doctor.

The bacterial theories of Louis Pasteur and Robert Koch have been important in eradicating the disease in the twentieth century. In 1884 Arthur Nicolaier found the bacillus in soil, and was able to produce the disease in animals. He found the same bacillus in human wounds. Shibasaburo Kitasato (1889) ob­tained the germ in pure culture. The tetanus toxoid was first used effectively during World War II. Immu­nization, along with the benefits of urbanization and industrialization, and a rise in the standειrd of liv­ing, have helped to eradicate the disease from devel­oped nations.

Another preventive measure evolved when in 1923 C. T. Broeck and J. H. Bauer showed that tetanus anti­toxin could cross the placenta. L. Nathan-Larrier, G. Ramon, and E. Grassett (1927) suggested that this could protect the newborn from tetanus by providing passive immunity. Later F. D. Schofield, G. R. West­brook, and V. M. Tucker (1961), studying the disease in New Guinea, and K. W. Newell and others in Colombia (1964), proved that immunizing a preg­nant woman with two or three injections of tetanus toxoid would decrease incidence of the disease. Unfor­tunately, it is difficult to provide such medical ser­vices to the people who need it most.

The World Health Organization continues to moni­tor the incidence of neonatal tetanus, to survey mor­tality rates of home and clinic deliveries, and to hold worldwide conferences to discuss means for improv­ing the care of newborns. Its goal is to eradicate neonatal tetanus by the year 2000.

Sally McMillen

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